Nancy L. Desmond

Synaptic correlates of associative potentiation/depression: an ultrastructural study in the hippocampus

Brief high-frequency trains delivered to the monosynaptic entorhinal cortical input to the dentate gyrus result in both increases and decreases of synaptic strength as a function of whether a particular afferent is active during conditioning (associative potentiation/depression). The present report concerns the effect of such brief, high-frequency conditioning trains upon the asymmetric synapses of the rat dentate gyrus molecular layer. Only those animals whose responses increased at least 50% following conditioning stimulation were included in the study. Additional animals were used for one-dimensional current source density analyses to localize the activated synaptic region. Double blind scoring procedures were used to classify and quantify electron micrographic data. Asymmetric synapses were scored as a function of their position in the molecular layer, spine head size and shape, and postsynaptic density length. All data were treated as inherently matched comparisons between the conditioned and control sides of each animal. The number of large, concave spine synapses with large postsynaptic densities significantly increases in the central zone of synaptic activation. Bordering this zone are regions with increases in synaptic number following conditioning, primarily due to an increased number of small spine synapses. The increased number of large, concave spine synapses in the central zone is postulated to mediate associative potentiation. The many small spine heads just adjacent to the zone of strongest synaptic activation may reflect synaptic depression evoked at synapses inactive during conditioning.

Granule cell dendritic spine density in the rat hippocampus varies with spine shape and location

The number of granule cell dendritic spines per micrometer of dendritic length in the dorsal and ventral leaves of the dentate gyrus was quantified using light microscopic-Golgi preparations of normal adult rats. Spines were counted in terms of 3 categories of spine form for the 3 afferent termination zones of the molecular layer and corrected for shading errors. Total spine density averaged 1.6 spines/micron of dendritic length in the dorsal leaf and 1.3 spines/micron of dendritic length in the ventral leaf. Statistically significant differences in spine density existed among the 3 shape categories. Variations in spine density occurred by shape category among the afferent termination zones.

Synaptic interface surface area increases with long-term potentiation in the hippocampal dentate gyrus.

The present study continues our attempt to understand the ultrastructural changes that accompany and may underlie long-term potentiation (LTP). This report describes changes with LTP in the surface area of the pre- and postsynaptic membrane apposition at the synapses formed by entorhinal cortical (EC) axons with granule cell dendritic spines of the dentate gyrus (DG). The electrophysiology and electron microscopy of the DGs from each animal followed conventional procedures. The trace length of the pre- and postsynaptic apposition was measured for identified asymmetric synapses in the dentate molecular layer. The total apposed membrane surface area per unit volume (Sv) was then computed for 4 categories of synaptic profiles for each third of the molecular layer. Statistical analysis of the Sv data used multivariate analyses of variance. Across the entire molecular layer, total apposed Sv does not change significantly with LTP. However, in the activated portion of the molecular layer, total apposed Sv increases significantly, reflecting a significant increase in the apposed Sv for the concave spine profiles there. For these spine profiles, the increased apposed Sv is due to the increased membrane area both at the postsynaptic density and beyond. The average apposed surface area per individual synapse also increases markedly with LTP. The present data support the hypothesis of coordinated pre- and postsynaptic anatomical changes with LTP in the EC-DG system.

Astrocytic volume fluctuates in the hippocampal CA1 region across the estrous cycle

The number of dendritic spine synapses in the hippocampal CA1 stratum radiatum fluctuates across the rat estrous cycle, being high on proestrus and low on estrus [20]. We hypothesized that the volume occupied by astrocytic processes changes in a complementary manner. The volume fraction of astrocytic processes was determined stereologically in CA1 s. radiatum and s. lacunosum-moleculare of cycling female rats. Consistent with our hypothesis, the volume fraction was significantly lower on the afternoon of proestrus than on the afternoon of estrus in both laminae.

Ovarian steroidal control of connectivity in the female hippocampus: an overview of recent experimental findings and speculations on its functional consequences.

Experimental evidence accumulated over the past 5 years clearly indicates that ovarian steroids regulate the number of synapses in the rat hippocampal CA1 region. When estradiol levels are high such as during proestrus and ovulation, the number of synapses is high; when estradiol levels are low such as during estrus, the number of synapses is low. Here we address three questions that are frequently raised by these phasic fluctuations in synapse number in a brain region to which cognitive functions are classically attributed. First, what neuronal signals might produce the changes in synapse number? Second, how are the hippocampal functions of memory encoding and cognitive mapping affected by fluctuating levels of ovarian steroids? Third, for mammals in general, what might be the ecological/cognitive significance of such changes? In this last section, we integrate some of the relevant human and rodent cognitive/behavioral literature and propose a hypothesis. Namely, by altering its quantitative connectivity, the female hippocampus is optimized for different cognitive/behavioral functions when the female is sexually receptive and ovarian steroid levels are high rather than when she is not receptive and steroid levels are low. The hippocampus thus shifts its optimal computational functions across the estrous/menstrual cycle. Hippocampus 7:239–245, 1997.

NMDA receptor antagonists block the induction of long-term depression in the hippocampal dentate gyrus of the anesthetized rat.

The present study tested the effect of two non-competitive NMDA receptor antagonists, ketamine and phencyclidine, on the induction of long-term depression (LTD) in the dentate gyrus of urethane-anesthetized rats. Both drugs blocked the induction of LTD as well as long-term potentiation (LTP). NMDA receptor activation thus seems to be required for the induction of both LTD and LTP in the dentate gyrus. High-intensity conditioning stimulation did not overcome the phencyclidine block of LTD. Strong, but brief, postsynaptic depolarization is apparently not the only event needed to trigger LTD.

Rapid development of somatic spines in stratum granulosum of the adult hippocampus in vitro

Somatic spines on granule cells have been observed occasionally in the adult rat dentate gyrus in vivo. Here we evaluate the appearance and formation of somatic spines in s. granulosum from adult rat hippocampal slices immediately after slice preparation, 45 min, 3 h, and 5 h later. Initially somatic spines are extremely rare but, after 3 h in vitro, they are readily apparent. Some of these somatic spines form asymmetric synapses that have a spherical vesicle-containing presynaptic bouton and a postsynaptic density. Other somatic spines lack a postsynaptic density and may also lack an apposed presynaptic bouton (free somatic spines) as observed in single thin sections. Both the number of these free somatic spines and the number of somatic spine synapses increase in a time-dependent manner. No somatic spines were observed on CA1 pyramidal cells in the same hippocampal slices. Electrophysiological observations indicate that the formation of somatic spine synapses on granule cells in the hippocampal slice occurs without any apparent granule cell activation. The trigger event for this very rapid synaptogenesis in the adult dentate gyrus remains to be determined.

Somatic ribosomal changes induced by long-term potentiation of the perforant path-hippocampal CA1 synapses

The present study quantified ribosomes, as an ultrastructural marker of neuronal protein synthesis, following long-term potentiation (LTP) in the hippocampal CA1 region in vitro. Sixty min after LTP-inducing, high-frequency stimulation of the perforant path, the total number of ribosomes, the number of polysomes, and the number of membrane-bound ribosomes increased significantly. These increases are a postsynaptic morphological correlate consistent with enhanced protein synthesis following the induction of LTP in the perforant path-CA1 system.

Strain and colony differences in the neurotoxic sequelae of MK-801 visualized with the amino-cupric-silver method

The strain and sex of a species under investigation may influence the animals physiological response to a variety of stimuli. Strain and sex differences are important considerations when evaluating animal models. In the rodent MK-801 model of schizophrenia, degenerative changes occur widely in the main olfactory system and in a number of cortical brain regions. In the present report, we compare the effects of MK-801 neurotoxicity in two strains of female rats and also two lines within each strain. The magnitude and regional extent of the neurodegeneration detected with the amino-cupric-silver method varied markedly both between the Sprague-Dawley and Wistar rat strains and also between two lines derived from each strain. For example, terminal degeneration occurred in layer VI of somatosensory cortex and the central extended amygdala in Sprague-Dawley but not Wistar rats. Moreover, MK-801 treatment led to somatodendritic degeneration in the dentate gyrus of the dorsal hippocampus and basolateral amygdala in Wistar rats from Charles River Laboratories but not those from Ferreyra Institute. There are thus both strain and intrastrain differences in the magnitude of the neurodegenerative response to MK-801 treatment. The differing neurotoxicity of MK-801 between rat strains and between lines within a strain may reflect genetic variation and/or differences in hepatic biotransformation and thus the bioavailability of the drug between strains and lines within a strain.